Processes for preparing sertraline

ABSTRACT

Provided are processes for the preparation of sertraline and sertraline hydrochloride.

RELATED APPLICATIONS

This application is a divisional application of allowed U.S. applicationSer. No. 11/361,456; which claims the benefit of U.S. ProvisionalApplication No. 60/656,134, filed Feb. 23, 2005; U.S. ProvisionalApplication No. 60/704,730, filed Aug. 1, 2005; Indian Application No.220/DEL/2006, filed Jan. 25, 2006, Indian Application No. 221/DEL/2006filed Jan. 25, 2006; U.S. Provisional Application No. 60/763,530, filedJan. 30, 2006; U.S. Provisional Application No. 60/763,531 filed Jan.30, 2006; U.S. Provisional Application No. 60/773,394, filed Feb. 14,2006; and, U.S. Provisional Application No. 60/773,567, filed Feb. 14,2006. The contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention encompasses processes for preparing sertraline andthe hydrochloride salt thereof.

BACKGROUND OF THE INVENTION

Sertraline hydrochloride, (1S-cis)-4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride, having the formula:

is approved under the trademark Zoloft® by the U.S. Food and DrugAdministration as a serotonin re-uptake inhibitor for the treatment ofdepression, obsessive-compulsive disorder, panic disorder andpost-traumatic disorder. Only cis sertraline is therapeutically active.

U.S. Pat. No. 4,536,518 (“the '518 patent”) describes the synthesis ofsertraline hydrochloride from sertralone having the following formula:

The reported process for synthesizing sertraline from sertralone has twosteps. First, sertralone is condensed with methyl amine in the presenceof an acid catalyst, to yield the Schiff base of sertralone,4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine(“ketimine”):

The imine is then reduced to sertraline. The formation of cis/transsertraline hydrochloride from sertralone is described in the followingreaction scheme:

The reduction process disclosed in the '518 patent involves thehydrogenation of ketimine concentrate at room temperature for two hoursover 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure).The product is reported to be a racemic mixture of the cis and transdiastereoisomers (“(±)-cis/trans-sertraline”) in a ratio ofapproximately 3 to 1.

International Publication WO 99/57093 reports a process of selectivehydrogenation with a palladium catalyst pretreated with an alkalihalide. The publication reports that the process of the '518 patent maylead to 10% of dechlorinated side products, while the process of thepublication has a “total amount of said contaminated by-products . . .below 0.5%.” With regard to the cis/trans ratio, the ratio provided is85-95% in the description of the invention.

U.S. Pat. No. 6,593,496 reports the preparation of ketimine by reactingsertralone with monomethylamine and either titanium tetrachloride ormolecular sieves. The hydrogenation illustrated in scheme 1 is carriedout with a palladium catalyst in THF.

US 2003/0105364 reports a process for obtaining optically puresertralone through chromatography. The examples do not illustratehydrogenation.

US 2003/0166970 reports a process for making (±)-sertraline with acis/trans ratio of greater than about 3:1 by hydrogenation of ketimineat a temperature of at least about 40° C. using a palladium or aplatinum catalyst.

Two publications, WO 01/30742 and WO 98/27050, report thestereoselective reduction of sertraline imine derivatives. Thepublication WO 01/30742 reports replacing the methyl group of ketiminewith an optionally substituted bulky benzyl group to increase the cis totrans ratio during hydrogenation, followed by the additional steps ofconverting the bulky group to a methyl group. Additionally, WO 01/30742reports that “The reduction may be performed using complex hydrides(e.g. NaBH₄) or by hydrogenation. Reduction performed by catalytichydrogenation tends to give better selectivity that reduction using thecomplex hydrides. For example, aliquots of N-[4-(3,4dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-benzylamine werereduced with NaBH₄ and Raney nickel/H₂ respectively, and subsequentlyreductively alkylated with formaldehyde, after which the cis/trans ratiowas analyzed. The result was a ratio of 53.8/46.2 using NaBH₄ comparedto 82.9/17.1 for Raney nickel/H₂ which clearly demonstrates theselectivity for the catalytic hydrogenation.”

WO 98/27050 reports obtaining sertraline by reducing an N-oxidederivative of the imine. According to Example 1, the N-oxide derivativeis hydrogenated with Raney nickel catalyst, while in Example 2 a 10%palladium on carbon is used as a catalyst. A cis product with an 81%yield is reported in both instances. According to WO 98/27050, theN-oxide group may then be removed by addition of HCl to the N-oxidecompound in ethanol.

WO 01/16089 discloses a process of reductive amination of sertralone tocis and trans sertraline. According to Example 1, sertralone is reducedin the presence of Raney nickel and methylamine. Example 1 reports ayield of 48-51% of the cis isomer.

Typically, hydrogenation of ketimine over Raney Nickel leads toformation of de-chlorinated impurities, where dechlorinated impuritiesare defined as the total amount of sertraline compounds wherein at leastone of the two chlorine atoms of the phenyl group is absent. The levelof impurities produced depends on the hydrogen pressure, reactiontemperature, and duration of hydrogenation. Therefore, control over thelevel of impurities on a commercial scale is extremely difficult.Furthermore, removal of these impurities is cumbersome due to the samesolubility pattern shared by sertraline and the impurities. Loss of thedesired material due to additional purification is also a significantobstacle to the hydrogenation process. There is a need in the art foradditional processes for hydrogenation of imines for preparation ofsertraline.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a process of preparingsertraline comprising the step of reducing ketimine with Raney Nickelunder a hydrogen atmosphere, wherein the ketamine is in a mixture withat least one halogenated hydrocarbon and at least one organic solvent.

In another embodiment, the present invention provides a process ofremoving titanium from ketimine comprising the steps of:

a) reducing ketimine with Raney Nickel under a hydrogen atmosphere inpresence of a titanium containing catalyst, wherein the ketamine is in amixture with at least one halogenated hydrocarbon and at least oneorganic solvent;

b) adding an additional amount of toluene to the reaction mixture;

c) filtering the mixture to obtain an organic layer;

d) washing the organic layer;

e) treating the organic layer with activated carbon followed byfiltration;

f) removing the toluene by distillation to obtain a residue;

g) combining the residue with cyclohexane; and

h) recovering the ketamine.

In another embodiment, the present invention provides a process forsertraline HCl comprising the steps of:

-   -   a) reducing sertraline-1-imine in a mixture with toluene and        1,2-dichlorobenzene with Raney Nickel under a hydrogen        atmosphere to obtain a racemic mixture;    -   b) combining toluene and D(−) mandeleic acid with the mixture to        precipitate crude sertraline mandelate;    -   c) recrystallizing the crude mandelate from ethanol to obtain a        purified mandelate salt;    -   d) converting the mandelate salt to the hydrochloride salt.

In another embodiment, the present invention provides sertraline or itshydrochloride salt thereof, having less than about 0.1% of dechlorinatedimpurities as measured by HPLC or GC.

In another embodiment, the present invention provides pharmaceuticalcomposition comprising sertraline HCl having less than about 0.1% ofdechlorinated impurities as measured by HPLC or GC and apharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

The term “dechlorinated impurities” refers to sertraline wherein atleast one of the two chlorine atoms of the phenyl group is absent. Thefollowing are examples of dechlorinated impurities:

Impurity A refers to the compound where chlorine at the 3-position isabsent. Impurity B refers to the compound where chlorine at the4-position is absent. Impurity C refers to the compound where bothchlorine atoms are absent.

The level of impurities in sertraline referred to throughout theapplication, i.e., “sertraline having less than about 0.1% ofdechlorinated impurities,” may be measured as area % by HPLC or GC.

In one embodiment, the invention encompasses a process for preparingsertraline by reducing ketimine with Raney Nickel, wherein the ketimineis in a mixture with at least one halogenated hydrocarbon and at leastone organic solvent. An advantage of this process is that a producthaving less than about 0.1% of dechlorinated impurities may be obtained.

Halogenated hydrocarbons may include cyclic or acyclic, saturated orunsaturated aliphatic or aromatic hydrocarbons. Preferred halogenatedhydrocarbons include those wherein the hydrocarbon is a C₁ to C₇aromatic or aliphatic hydrocarbon. The halogenated hydrocarbon caninclude any compound wherein one or more hydrogen atoms (preferably fromone to three, more preferably one or two) of the C₁ to C₇ aromatic oraliphatic hydrocarbon is substituted with a halo group selected fromfluoro, chloro or bromo, with chloro being particularly preferred.

Halogenated hydrocarbons for use in the present invention includeshalogenated aromatic hydrocarbons wherein the hydrocarbon is C₆ or C₇,e.g. benzene or toluene. The benzene and toluene may be halogenated(preferably with one to three, more preferably one or two halo,preferably chloro, groups) either in the aromatic ring or in the methylgroup of toluene.

Also preferred are halogenated hydrocarbons wherein the hydrocarbon isan aliphatic hydrocarbon selected from the group consisting of C₁ to C₄alkanes, C₂ to C₄ alkenes (preferably C₂, i.e. ethene) or a C₄ diene.Halogenated hydrocarbons for use in the present invention includehalogenated aliphatic hydrocarbons wherein the hydrocarbon is a C₁ to C₄alkane, alkene or diene, wherein at least one (preferably one to six,more preferably one to three, and most preferably one or two) hydrogenatoms are replaced by fluoro, chloro or bromo, preferably chloro orfluoro, with chloro being most preferred. The most preferred halogenatedhydrocarbons are chlorobenzene, o-, m- or p-dichlorobenzene,dichloromethane, and o- or p-chlorotoluene.

The halogenated hydrocarbon may be present in an amount sufficient toreduce or ameliorate dehalogenation Preferably, the halogenatedhydrocarbon is present in an amount of about 0.01 mol to about 3.0 molequivalent of the ketimine, more preferably about 0.5 mol to about 2.0mol equivalent, and most preferably about 1.0 mol equivalent. Theconcentration of halogenated hydrocarbons with respect to Ketimine ispreferably in the range of about 20% to about 50% weight by volume andmost preferably about 50% weight by volume).

Suitable organic solvents are those in which ketimine is soluble. Theexamples provide many different suitable solvents. Preferably, theorganic solvent is a C₁-C₄ alcohol, C₃-C₆ ester, C₆-C₁₂ aromatichydrocarbon, C₂-C₈ ether, or C₃-C₇ amide or mixtures thereof. Morepreferably, the organic solvent is methanol, ethanol, isopropanol,toluene, tetrahydrofuran, ethyl acetate, dimethylformamide or mixturesthereof. In one embodiment, the organic solvent is a mixture of tolueneand methanol.

Any Raney Nickel catalyst commonly used in the art may be used to reducethe ketimine and form sertraline. Examples of suitable catalystsinclude, but are not limited to, Kalcet™ 8030, Kalcet™ 1961, Kalcet™3801, Kalcet™ 9031, or Kalcet™ 2921 (Monarch Catalyst Pvt. Ltd,Dombivli(E), Thane-421 203, India). Preferably, the catalyst is Kalcet™8030, Kalcet™ 1961, or Kalcet™ 3801. The more preferred catalyst isKalcet™ 8030. Table 1 exemplifies the ratios of cis:trans sertralineisomers formed based on the type of Raney Nickel used. TABLE 1 RaneyNickel catalyst diastereomeric purity (% of Cis and Trans) Raney NickelDiastereomeric purity, % by GC Example catalyst cis isomer trans isomer1 Kalcet ™ 8030 91 8.34 2 Kalcet ™ 1961 89.9 8.8 3 Kalcet ™ 3801 87.211.8 4 Kalcet ™ 9031 86.5 12.2 5 Kalcet ™ 2921 89.5 9.9

The following table provides detailed information about the contents ofthese catalysts: Standard Specifications NB Nickel Activity Bulk S. No.Catalyst Grade pH Content Test Density 1. KALCET-3801 9-10.5 90-92% Min50-  0.7-0.85 60(H₂) gram/ml(cc) ml/gm/min. 2. KALCET-2921 9-10.5 86-88%Min 55- 0.5-0.6 65(H₂) gram/ml(cc) ml/gm/min. 3. KALCET-1961 9-10.586-88% Min 55- 0.5-0.6 60(H₂) gram/ml(cc) ml/gm/min. 4. KALCET-80309-10.5 86-88% Min 40- 0.70-0.78 45(H₂) gram/ml(cc) ml/gm/min. 5.KALCET-9031 9-10.5 88-90% Min 55- 0.70-0.78 65(H₂) gram/ml(cc)ml/gm/min.

Hydrogenation of the ketimine is preferably performed at about 3 kg/cm²to about 9 kg/cm², more preferably at about 5 kg/cm² to about 6 kg/cm²over pressure of hydrogen at a suitable temperature for a sufficientperiod. Preferably, hydrogenation is carried out for about 2 to about 12hours, more preferably about 5 hours to about 10 hours, and mostpreferably about 6 to about 7 hours. The reaction may be performed at atemperature of about 10° C. to about 40° C., preferably about 25° C. toabout 35° C., and most preferably about 28° C. to about 30° C. Thecatalyst may be removed by any suitable method such as filtration. Thefilter cake may be washed with additional organic solvent afterfiltration.

The hydrogenated product, which contains sertraline and its isomer(s),may then be converted to sertraline HCl, in various manners. Forexample, hydrochloric acid may be provided as aqueous HCl, HCl gas, orHCl in a suitable organic solvent. In one embodiment, aqueous HCl (33%)in an amount of about 1 mol to about 2 mol equivalents, more preferablyabout 1.5 mol, is added to sertraline. Alternatively, HCl gas is bubbledinto a solution of sertraline, which may be in the solvent used duringthe reduction of ketimine, or another suitable solvent such as, forexample, n-butanol.

Sertraline hydrochloride may also be crystallized into variouspolymorphic forms, such as those disclosed in U.S. Pat. Nos. 6,500,987,6,495,721 and 6,452,054, all incorporated herein by reference. Forexample, Sertraline hydrochloride Form II is prepared by contactingsertraline in a suitable solvent with hydrogen chloride gas at atemperature of about 0° C. to about 60° C., more preferably at about 30°C. to about 50° C., even more preferably at about 30° C. to about 45°C., and most preferably at about 40° C. to about 45° C. Salts such assertraline mandelate may also be used as a starting material. Sertralinemay be present in a solution or a slurry. Since sertraline is highlysoluble in solvents such as n-butanol, a solution is preferred. Examplesof suitable solvents are disclosed in U.S. Pat. Nos. 6,495,721 and6,500,987.

Preferably, the desirable cis sertraline hydrochloride isomer isseparated from the undesirable trans isomer. In one embodiment, theseparation is carried out after conversion to the HCl salt. Opticalresolution of the (±)-cis/trans-sertraline hydrochloride may be carriedout in an appropriate organic solvent, such as ethanol, isopropanol,methanol, n-butanol, or iso-butanol. Ethanol is preferred.

In another embodiment, the separation is carried out before conversionto the HCl salt. This scheme entirely eliminates an intermediate in thescheme, namely the HCl salt of the trans isomer. Since resolution iscarried out with sertraline as opposed to a sertraline HCl salt,non-polar solvents are preferred, particularly C₆ to C₁₂ aromatic andsaturated hydrocarbons, such as toluene, xylene, benzene andcyclohexane.

Regardless of the order, the resulting crude (+)-cis-sertralinemandelate is recrystallized in one embodiment to increase the purity ofthe product. Appropriate organic solvent include ethanol, isopropanol,methanol, n-butanol, or iso-butanol. Ethanol is preferred. Otheroptically active salts may also be used for resolution, such as, thoseobtained by reaction with tartaric acid, camphor sulphonic acid andlactic acid.

To obtain the HCl salt, the recrystallized (+)-cis-sertraline-mandelateis dissolved in organic solvent and the mandelic acid is removed withbase, such as by washing the organic solution with an aqueous basicsolution, e.g., 10-20% sodium hydroxide (NaOH) solution, or 10-20%potassium (KOH) solution. Generally, bases such as potassium hydroxide,sodium hydroxide, sodium carbonate (Na₂CO₃) and sodium bicarbonate(NaHCO₃) may be used. The (+)-cis-sertraline free base is isolated,dissolved in an appropriate organic solvent, and is treated withhydrochloric acid to give (+)-cis-sertraline hydrochloride. Details ofHCl salt preparation are provided above.

The present invention provides a synthetic scheme suitable forpreparation of sertraline hydrochloride without synthesis of isomericmixture of N-Methyl-4-(3,4-Dichlorophenyl),1,2,34-tetrahydro-1-naphthalenamine hydrochloride (Key intermediate).The following preferred embodiment illustrates this scheme:

To resolve the product of the hydrogenation, sertraline mother liquor isdistilled to obtain a residue. Toluene and D(−)Mandelic acid are thencombined with the residue. The resulting crude mandelate salt isrecrystallized in ethanol to get pure of sertraline mandelate. Therecrystallized (+)-cis-sertraline-mandelate can then be liberated andconverted to the HCl salt as described above. This reaction schemeproduces a product of high quality in high yields: TABLE 1 US 6809221This Process Steps (w/w) (w/w) Schiff's Base 1.01 0.95 Sertraline Base —— Sertraline Mandelate 0.53 0.60 Sertraline Mandelate (Pure) 0.79 0.85Overall yield 0.42 0.48 Purity Limits Product Cis (1S, 4S) NLT-98.0%99.7-99.9% 99.64% Cis (1R, 4R) NMT-0.3% ≅0.07% Nil Trans Isomer NMT-0.3% 0.20% 0.185% DCS-1 NMT-0.2% Complies Complies DCS-2 NMT-0.2% CompliesComplies

The ketimine used in the process of the present invention may beprepared from sertralone. Sertralone may be condensed with methyl aminein the presence of an acid catalyst. Any suitable acid catalyst known inthe art may be used, such as, for example, TiCl₄. See, e.g., U.S. Pat.No. 4,546,518.

The invention further encompasses a process of removing titanium fromthe ketamine formed from condensing sertralone with methyl amine in thepresence of TiCl₄. The process of removing titanium comprises the stepsof a) reacting sertralone with methylamine in a C₆ to C₁₂ hydrocarbon inthe presence of TiCl₄ to obtain ketamine b) adding an additional amountof toluene to the reaction mixture, c) filtering the mixture to obtainan organic layer, d) washing the organic layer, e) treating the organiclayer with activated carbon followed by filtration, f) removing thetoluene by distillation to obtain a residue, g) combining the residuewith cyclohexane; h) recovering the ketamine.

The organic solvent in the reaction mixture is preferably a C₆-C₁₂aromatic hydrocarbon. More preferably, the organic solvent is toluene.The reaction is preferably heated to a temperature of about 45° C. toabout 60° C. and stirred for about 20 minutes to about one hour.

Preferably, the reaction mixture is filtered through a filter such as aCelite or hyflo filter to obtain a cake, and the cake is then washedwith an aqueous solvent, preferably water.

The organic layer is then treated with activated carbon. Preferably, theorganic layer is heated to about 40° C. to 55° C. and then treated with5% activated carbon for at least about 30 minutes. The activated carboncan be removed by filtration, such as by filtration through a Celite orhyflo filter. After the removal of activated carbon by filtration, theresulting cake may optionally be washed again with organic solvent, suchas toluene.

Ketimine can be isolated by removing the organic solvent, such as bydistillation under vacuum. A C₆ to C₁₂ saturated hydrocarbon, such ascyclohexane or n-hexane is added to the residue to aid recovery of theproduct. The solid is then be filtered and dried, such as under a vacuum(generally pressure below 100 mmHg).

In one embodiment, the present invention provides for sertraline of itsHCl salt having a cis/trans ratio of about 9:1. In another embodiment,the present invention provides for sertraline of its HCl salt havingless than about 0.1% of dechlorinated impurities as measured by HPLC orGC. Such product may be produced by carrying out the processes of thepresent invention.

Pharmaceutical compositions containing sertraline, orpharmaceutically-acceptable salts thereof, having less than about 0.1%of dechlorinated impurities and/or a cis/trans ratio of greater thanabout 9:1, and at least one pharmaceutically-acceptable excipient arealso encompassed by the present invention.

Pharmaceutically-acceptable excipients are added to the pharmaceuticalcomposition for a variety of purposes. For example, diluents increasethe bulk of a solid pharmaceutical composition, and may make apharmaceutical dosage form containing the composition easier for thepatient and care giver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelatinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants may be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which may cause the productto have pitting and other surface irregularities. A lubricant may beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the compositioninclude maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaricacid, ethyl maltol and tartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions, sertraline hydrochloride and anyother solid excipients are dissolved or suspended in a liquid carriersuch as water, vegetable oil, alcohol, polyethylene glycol, propyleneglycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions include, for example,gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus,pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetylalcohol.

Liquid pharmaceutical compositions may also contain a viscosityenhancing agent to improve the mouth-feel of the product and/or coat thelining of the gastrointestinal tract. Such agents include acacia,alginic acid bentonite, carbomer, carboxymethylcellulose calcium orsodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatinguar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylenecarbonate, propylene glycol alginate, sodium alginate, sodium starchglycolate, starch tragacanth and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

A liquid composition may also contain a buffer such as gluconic acid,lactic acid, citric acid or acetic acid, sodium gluconate, sodiumlactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts used may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions include powders, granulates, aggregates andcompacted compositions. The dosages include dosages suitable for oral,buccal, rectal, parenteral (including subcutaneous, intramuscular, andintravenous), inhalant and ophthalmic administration. Although the mostsuitable administration in any given case will depend on the nature andseverity of the condition being treated, the most preferred route isoral. The dosages may be conveniently presented in unit dosage form andprepared by any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges, as well as liquid syrups,suspensions and elixirs.

The dosage form may be a capsule containing the composition, preferablya powdered or granulated solid composition, within either a hard or softshell. The shell may be made from gelatin and optionally contain aplasticizer such as glycerin and sorbitol, and an opacifying agent orcolorant.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried and thenscreened and/or milled to the desired particle size. The granulate maythen be tableted, or other excipients may be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules may subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.The proper use of these and other excipients in direct compressiontableting is known to those in the art with experience and skill inparticular formulation challenges of direct compression tableting.

A capsule filling may comprise any of the aforementioned blends andgranulates that were described with reference to tableting, however,they are not subjected to a final tableting step.

Preferably, the pharmaceutical formulations are solid dosage forms inthe form of a tablet for the oral administration of sertralinehydrochloride. The sertraline hydrochloride used for preparing a tabletmay be in the form of fine crystals. Preferably, the fine crystals havea particle size distribution such that 100% of the particles are below200 microns, more preferably below 100 microns and most preferably belowabout 50 microns.

The pharmaceutical composition may be used to inhibit serotonin reuptakein a mammal by administration to a mammal in need thereof.

Although certain presently preferred embodiments of the invention havebeen described herein, it will be apparent to those skilled in the artto which the invention pertains that variations and modifications of thedescribed embodiments may be made without departing from the spirit andscope of the invention. Accordingly, it is intended that the inventionbe limited only to the extent required by the appended embodiments andthe applicable rules of law.

1. Chromatographic Purity (by GC)

-   -   Column: DB-17 (30 m×0.53 mm×1.0 μm)    -   J & W P/N 125-1732 or equivalent column    -   Detector: FID

Initial oven temperature: 215° C.

Initial time: 26 min.

Initial rate: 5° C./min.

Final oven temperature: 250° C.

Final time: 7 min.

Injector temperature: 160° C.

Detector temperature: 300° C.

Flow (helium): 14.8 ml/min

Injection volume: 1 μL

Diluent: Hexane

Temperature and flow rate may be varied in order to achieve the requiredsystem suitability.

2.1 System Suitability Preparation:

Weigh about 5 mg each of Sertraline Hydrochloride Racemate and2,3-Iso-Sertraline standard into 25 ml test tube add 4 ml of 2.5%ammonium hydroxide solution followed by exactly 10 ml of n-Hexane. Shakewell wait for phase separation and inject the organic (upper) layer.

2.2 Sample Preparation:

Weigh about 20 mg Sertraline Hydrochloride sample into a 25 ml testtube. Add 5 ml of 2.5% ammonium hydroxide solution followed by exactly10 ml of n-hexane. Shake well wait for phase separation and inject theorganic (upper) layer.

2.3 System Suitability Criteria

The resolution factor between the Sertraline peak and trans-Sertralineof not less than 1.7 should be achieved.

Typical retention times are 16.3 minutes for Sertraline and 17.4 minutesfor trans-Sertraline.

2.4 Procedure

Inject equal amount of blank (Hexane) and sample in the chromatograph,continuing the chromatogram upto the end of the temperature gradient.Determine the areas for all peaks in each solution using a suitableintegrator. Ignore the peaks due to blank. The relative retention timesof the impurities are as follows Name RRT DCS-3 0.29 DCS-1 0.51 DCS-20.54 2,3-Iso SRT 0.92 Sertraline 1.00 Trans-Sertraline 1.07 Sertralone1.27 Schiffs Base 1.55

EXAMPLES Example 1N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)naphthalenylidene]methanamine

100 g of Sertralone and 400 ml Toluene are charged into a reactionvessel fitted with a stirrer and gas inlet. The stirrer is started andthe suspension is cooled to −15 to −10° C. A monomethylamine solution(72.4 g in 300 ml Toluene, 6.8 Mole) cooled to about −15 to −10° C. iscombined with the sertralone suspension. Titanium Tetrachloride (17 ml,0.45 mole) is added while the temperature is maintained at about −15 to−10° C. The temperature is slowly raised to about 55° C. to 60° C. andthe mixture is stirred for about one hour. The product is more than 98%(GC Purity).

Toluene (200 ml) is added and the reaction is stirred for 20 minutes atabout 55° C. to 60° C. The reaction mass is filtered through Celite andthe cake is washed with 100 ml Toluene and filtered again. The toluenelayer was washed with water (3×250 ml) and separated. The toluene layerwas heated to about 40° C. to 55° C. and treated with 5% Charcoal for 30minutes before being filtered through hyflo. The hyflo bed was washedwith Toluene (25 ml) and then the toluene was distilled at about 45° C.to 55° C. under vacuum. After complete removal of toluene, cyclohexane(150 ml) was added. The solid was filtered and dried at 50° C. for 2hours under vacuum. Kf=0.2.

Hydrogenation of the Schiff's Base (ketimine) obtained above byfollowing the procedure in Example 3 gave a product of 93.77% Cis, 4.89%Trans, 1.05% Sertralone, 0.35% Schiff's Base. DCS-1 and DCS-2 are notdetected.

Example 2N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)naphthalenylidene]methanamine

100 gms of Sertralone and 400 ml Toluene are charged into a reactionvessel fitted with a strirrer and gas inlet. The stirrer is started andthe suspension is cooled to about −15° C. to −10° C. A monomethylaminesolution (72.4 g in 300 ml Toluene, 6.8 Mole) cooled to about −15° C. to−10° C. is combined with the suspension. Titanium Tetrachloride (17 ml,0.45 mole) is added while the temperature is maintained at about −15° C.to −10° C. The temperature is slowly raised to about 55° C. to 60° C.and the mixture is stirred for 1 hour. The product is more than 98% (GCPurity).

Toluene (200 ml) is added and the reaction is stirred for 20 minutes atabout 55° C. to 60° C. The reaction mass is filtered through Celite andthe cake is washed with 100 ml toluene. The toluene layer was washedwith water (3×250 ml) and separated. The toluene was distilled at 45° C.to 55° C. under vacuum. After complete removal of toluene, cyclohexane(150 ml) was added. The product was filtered and dried at 50° C. for 2hours under vacuum. Kf=0.2.

Hydrogenation of the Schiff's Base (ketimine) obtained above byfollowing the procedure in Example 3 gave a product of 94.66% Cis, 3.82%Trans, 0.62% Sertralone, 0.38% Schiff's Base. DCS-1 and DCS-2 are notdetected

Example 3(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30°C. The catalyst is removed by filtration and the cake is washed with 50ml methanol. The cis to trans ratio is 87 to 89/9 to 13. The amount ofdehalogenated by product is <0.1%. Sertraline racemate free base thusformed is treated with hydrochloric acid (24 ml, 33%) and predominantlyisomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%,dehalogenation product<0.1%, yield 0.86 to 0.88%].

Example-4(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, chlorobenzene as dehalogenation inhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and chlorobenzene (25 ml) are chargedinto a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm²over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. Thecatalyst is removed by filtration and the cake is washed with 50 mlmethanol. The cis to trans ratio is 87-89/9-13. The amount ofdehalogenated by product is <0.1%. Sertraline racemate free base thusformed is treated with hydrochloric acid (24 ml, 33%) and predominantlyisomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%,dehalogenation product<0.1%, yield 0.86 to 0.88%].

Example-5(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in toluene, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), toluene (300 ml), RaneyNickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged intoa reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm² overpressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalystis removed by filtration and the cake is washed with 50 ml methanol. Thecis to trans ratio is 75 to 80/25 to 20. The amount of dehalogenated byproduct is <0.1%. Sertraline racemate free base thus formed is treatedwith hydrochloric acid (24 ml, 33%) and predominantly isomer ofsertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenationproduct<0.1%, yield 0.80 to 0.82%].

Example-6(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in tetrahydrofuran, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), tetrahydrofuran (300ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C.The catalyst is removed by filtration and the cake is washed with 50 mltetrahydrofuran. The cis to trans ratio is 85 to 87/15 to 13. The amountof dehalogenated by product is <0.1%. Sertraline racemate free base thusformed is treated with hydrochloric acid (24 ml, 33%) and predominantlyisomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%,dehalogenation product<0.1%, yield 0.75 to 0.78%].

Example-7(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in Ethyl Acetate, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), Ethyl acetate (300 ml),Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C.The catalyst is removed by filtration and the cake is washed with 50 mlethyl acetate. The amount of dehalogenated by product is <0.1%.Sertraline racemate free base thus formed is treated with hydrochloricacid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate isfiltered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.78 to0.80%].

Example-8(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in dimethylformamide, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), dimethylformamide (300ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 12 to 13 hrs at about 28 to 30° C.The catalyst is removed by filtration and the cake is washed with 50 mlmethanol. The amount of dehalogenated by product is <0.1%. Sertralineracemate free base thus formed is treated with hydrochloric acid (24 ml,33%) and predominantly isomer of sertraline HCl racemate is filtered[Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.72 to 0.75%].

Example-9(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in ethanol, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), ethanol (300 ml), RaneyNickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged intoa reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm² overpressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalystis removed by filtration and the cake is washed with 50 ml ethanol. Thecis to trans ratio is 82 to 85/18 to 15. The amount of dehalogenated byproduct is <0.1%. Sertraline racemate free base thus formed is treatedwith hydrochloric acid (24 ml, 33%) and predominantly isomer ofsertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenationproduct<0.1%, yield 0.80 to 0.82%].

Example-10(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in isopropyl alcohol, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), IPA (300 ml), RaneyNickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged intoa reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm² overpressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalystis removed by filtration and the cake is washed with 50 ml EPA. Theamount of dehalogenated by product is <0.1%. Sertraline racemate freebase thus formed is treated with hydrochloric acid (24 ml, 33%) andpredominantly isomer of sertraline HCl racemate is filtered [Cis>95%,trans<5%, dehalogenation product<0.1%, yield 0.80 to 0.82%].

Example-11(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, DCM as dehalogenation inhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and DCM (12.5 ml) are charged into areaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm² overpressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalystis removed by filtration and the cake is washed with 50 ml methanol. Theamount of dehalogenated by product is <0.1%. Sertraline racemate freebase thus formed is treated with hydrochloric acid (24 ml, 33%) andpredominantly isomer of sertraline HCl racemate is filtered [Cis>95%,trans<5%, dehalogenation product<0.1%, yield 0.76%].

Example-12(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, o-chlorotoluene as dehalogenation inhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and o-chlorotoluene (50 ml) are chargedinto a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm²over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. Thecatalyst is removed by filtration and the cake is washed with 50 mlmethanol. The amount of dehalogenated by product is <0.1%. Sertralineracemate free base thus formed is treated with hydrochloric acid (24 ml,33%) and predominantly isomer of sertraline HCl racemate is filtered[Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.76%].

Example 13 Salt formation in 18% reducing quantity of Methanol(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30°C. The catalyst is removed by filtration and the cake is washed with 50ml methanol. After distillation of 18% Methanol, sertraline racematefree base thus formed is treated with hydrochloric acid (24 ml, 33%) andpredominantly isomer of sertraline HCl racemate is filtered [Cis 97.25%,trans 2.30%, Sertralone 0.05%, Schiff's base not detected,dehalogenation product (DCS-1 0.07% DCS-2 0.09%), yield 0.93 w/w].

Example 14 Salt formation in 20% reducing quantity of Methanol(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and O-dichlorobenzene (50 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30°C. The catalyst is removed by filtration and the cake is washed with 50ml methanol. After distillation of 20% methanol, sertraline racematefree base thus formed is treated with hydrochloric acid (24 ml, 33%) andpredominantly isomer of sertraline HCl racemate is filtered [Cis 98.59%,trans 1.57%, Sertralone 0.03%, Schiffs base not detected, dehalogenationproduct (DCS-1 0.09% DCS-2 0.04%), yield 0.97 w/w].

Example 15 Salt formation in 22% reducing quantity of Methanol(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30°C. The catalyst is removed by filtration and the cake is washed with 50ml methanol. After distillation of 22% Methanol, sertraline racematefree base thus formed is treated with hydrochloric acid (24 ml, 33%) andpredominantly isomer of sertraline HCl racemate is filtered [Cis 97.77%,trans 1.41%, sertralone 0.06%, Schiff's base not detected,dehalogenation product (DCS-1 0.08% DCS-2 0.05%), yield 1.01 w/w].

Example 16 Salt formation in 40% reducing quantity of Methanol(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30°C. The catalyst is removed by filtration and the cake is washed with 50ml methanol. After distillation of 40% methanol, sertraline racematefree base thus formed is treated with hydrochloric acid (24 ml, 33%) andpredominantly isomer of sertraline HCl racemate is filtered [Cis 97.96%,trans 1.89%, sertralone not detected, Schiff's base not detected,dehalogenation product (DCS-1 0.01%, DCS-2 0.03%), yield 0.95 w/w].

Example-17 Optical Resolution of Sertraline Hydrochloride

(±)-Sertraline hydrochloride (5 g) was dissolved in ethanol (20 mL) andKOH powder (85%) was added to the solution. The slurry was stirred atroom temperature for 2.5 hrs. After stirring the solids were removed byfiltration and the solution was treated with D-(−)-mandelic acid (2.66g). Precipitation occurred and the stirring was continued for 24 hours.(+)-Sertraline-mandelate was isolated by filtration and washed withethanol and then dried to yield 2.70 g of (+)-sertraline-mandelate.

Example-18 Preparation of Sertraline Hydrochloride Form II (IndustrialScale)

Sertraline base (27 kg) was dissolved in 105 kg of n-butanol. Thesolution was treated for 1 hour with 1 kg carbon at 40 to 45° C. andfiltered and washed with 25 kg n-butanol. The solution was reheated to40-45° C. and the achieved temperature was kept constant during the gasflow and filtration. Hydrogen chloride gas was added at the rate of4.5-5 kg/hr for the duration of 1 hour until pH 0.5 or less was reached.Immediately thereafter, the slurry was filtered at 40-45° C. The cakewas washed with 25 kg of n-butanol, and dried for about 4 hours at 80°C. The yield was 70% (21.2 kg).

Example 19(a) Preparation of(1s-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride (in methanol, o-dichlorobenzene as dehalogenationinhibitor)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml),Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) arecharged into a reaction vessel. The mixture is hydrogenated at 5 to 6kg/cm² over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30°C. The catalyst is removed by filtration and the cake is washed with 50ml methanol. The cis to trans ratio is 87 to 89/9 to 13. The amount ofdehalogenated by product is <0.1%.

Example 19(b) Preparation of(1S,4S)—N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-methyl-1-naphthalenamineMandelate

Sertraline Racemate free base thus formed is distilled out to getresidue and added fresh Toluene. This solution then heated to 75-80° C.and added D(−)Mandelic Acid. Heated to reaction mass to 75-80° C. for 30to 45 Minutes and finally cooled to 14-25° C. The obtained crudeMandelate salt having SS Sertraline Mandelate>95% RR isomer<2%, SR/RSisomer<2.5%, yield 0.6 w/w.

The obtained curde Mandelate dissolved in 25 to 28 volume hot absoluteethanol and heated for 30 to 40 Minute at 78° C. (+2° C.). After coolingon crystallization it gives pure Sertraline Mandelate Cis(1S,4S)—N-methyl-4-(3,4-dichlorophynyl),1,2,3,4-tetrahyro-1-naphthalenamineMandelate>99%, RR isomer<0.2%, RS/SR isomer<0.2%.

Example 19(c) Preparation of Cis(1S,4S)—N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenaminehydrochloride

The recrystallized (+)-cis-sertraline-precipitant, e.g.,(+)-cis-sertraline-mandelate, is dissolved in organic solvent and themandelic acid is removed with base, such as, by washing the organicsolution with aqueous basic solutions, e.g., 10-20% sodium hydroxide(NaOH) solution, or 10-20% potassium (KOH) solution. The(+)-cis-sertraline free base is isolated, dissolved in an appropriateorganic solvent, and is treated with hydrochloric acid.(+)-cis-Sertraline hydrochloride is precipitated and dried to give(+)-cis-sertraline hydrochloride.

1. Sertraline or its hydrochloride salt thereof, having less than about0.1% of dechlorinated impurities as measured by HPLC or GC.
 2. Apharmaceutical composition comprising sertraline HCl having less thanabout 0.1% of dechlorinated impurities as measured by HPLC or GC and apharmaceutically acceptable excipient.